Amyotrophic Lateral Sclerosis (ALS) is the most common motor neuron degenerative disease, in which motor neuron degeneration and death result in progressive paralysis and eventual death by respiratory failure. ALS is a particular concern for veterans as several studies indicated that military service is associated with increased risk of ALS. At present, there are no effective treatments for this debilitating disease and the development of effective therapies is impeded by the lack of suitable targets, particularly for sporadic ALS, which represents the majority cases that do not have identifiable genetic causes. Glutathione peroxidase 4 (Gpx4) is a selenoprotein glutathione peroxidase important in protecting membranes against oxidative damage. Recently, Gpx4 was identified as a key inhibitor of ferroptosis, an oxidative, iron- dependent cell death mechanism different from other cell death mechanisms such as apoptosis. Serendipitously, we discovered that Gpx4 is a key protector of spinal motor neurons. In addition, our preliminary results indicated that overexpression of Gpx4 extended lifespan of ALS mice. Our preliminary results further suggested that the ferroptosis inhibition function of Gpx4 is important for motor neuron protection. Built upon these exciting results, this project is designed to test the therapeutic potential of Gpx4 overexpression and ferroptosis inhibition for ALS. The overall hypothesis to be tested in this project is: Gpx4 overexpression and ferroptosis inhibition can ameliorate motor neuron degeneration and retard disease of ALS. The hypothesis will be tested by three specific aims. Aim 1 is to determine whether Gpx4 overexpression improves locomotor function and attenuates motor neuron degeneration in ALS mice. Aim 2 is to examine the role of ferroptosis inhibition in retarding disease in ALS mice. Aim 3 is to determine the effect of Gpx4 overexpression mediated by viral delivery in retarding disease of ALS mice. The results from this project will provide novel insights into the mechanism of motor neuron degeneration in ALS, and importantly, could lead to new therapeutic strategies for ALS.